1. Vutrisiran treatment reduced the risk of death and recurrent cardiovascular events compared to placebo in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM).
2. Secondary benefits included preserved functional capacity, improved quality of life, and reduced progression of heart failure symptoms over 42 months.
Evidence Rating Level: 1 (Excellent)
Study Rundown: ATTR-CM is a systemic disease secondary to transthyretin protein folding defects. It leads to progressive organ failure and mortality. RNA interference agents are gaining popularity in genetic diseases related to protein misfolding. Accordingly, this randomized, double-blind, placebo-controlled clinical trial (HELIOS-B) evaluated vutrisiran. It is an RNA interference therapeutic agent specifically targeted at TTR messenger RNA for the treatment of ATTR-CM. In this study, a total of 655 patients were randomized to receive either vutrisiran (25 mg every 12 weeks) or a placebo control. Vutrisiran significantly lowered the composite risk of death from any cause and recurrent cardiovascular events in the overall and monotherapy populations as compared to the placebo control. Improvements in the six-minute walk test and Kansas City Cardiomyopathy Questionnaire–Overall Summary score were observed at 30 months in the treatment as compared to the placebo. Adverse events were similar between groups, with most events being mild to moderate. The study limitations included the allowance of tafamidis as a background therapy, which precluded direct comparisons, and a predominance of male and white participants. In summary, vutrisiran represents a promising new treatment for patients with ATTR-CM.
Click to read the study in NEJM
In-Depth [randomized controlled trial]: The HELIOS-B trial was a phase three, randomized placebo-controlled trial that enrolled 655 patients aged between 18 to 85 years with ATTR-CM (wild-type or variant), stratified by tafamidis use. 326 patients were randomized to vutrisiran (25 mg subcutaneously every 12 weeks) and 329 patients were randomized to placebo. The primary endpoint was the composite of death and recurrent cardiovascular events. In the overall population, vutrisiran reduced the primary endpoint risk (Hazard Ratio [HR], 0.72; 95% Confidence Interval [CI], 0.56–0.93; p=0.01), with consistent results in the monotherapy population (HR, 0.67; CI, 0.49–0.93; p=0.02). In addition, vutrisiran reduced the risk of death from any cause over 42 months (HR, 0.65; CI, 0.46–0.90; p=0.01). At 30 months, the least-squares mean difference in the 6-minute walk test was 26.5 m (CI, 13.4–39.6; p<0.001), and the mean Kansas City Cardiomyopathy Questionnaire score difference was 5.8 points (CI, 2.4–9.2; p<0.001). NYHA class stability or improvement at 30 months was observed in 68% of the vutrisiran group compared to 61% in the placebo group (Difference CI 1.3–16.1; p=0.02). Adverse events were comparable between groups (99% in the vutrisiran group vs. 98% in placebo). Serious adverse events occurred in 62% of the vutrisiran group and 67% of the placebo group. No new safety concerns were identified. These findings highlight vutrisiran’s efficacy in reducing mortality and cardiovascular events, preserving physical function, and improving quality of life in ATTR-CM patients.
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